Ireland-Claisen Rearrangement Research Articles

A New Variant of Fused Cyclic Ether Synthesis Based on Ireland-Claisen Rearrangement and RCM

A new variant of fused cyclic ether synthesis based on Ireland-Claisen rearrangement and ring-closing olefin metathesis (RCM) was developed. The Ireland-Claisen rearrangement of a (Z)-3-alkoxyprop-2-en-1-yl glycolate ester having a cyclic ether on the oxygen at C3 of the (Z)-prop-2-en-1-yl group stereoselectively produced an anti-alpha,beta-dialkoxyester, which was successfully transformed to a fused bicyclic ether via a reaction sequence including RCM.

A stereoselective method for the construction of the C8′–O–C6″ ether of nigricanoside-A: synthesis of simple models for the C20 lipid chain/galactosyl glycerol segment

A method for the stereoselective construction of the C8′–O–C6″ ether of nigricanoside-A, an antimitotic natural product from the green alga Avrainvillea nigricans , has been developed based on chirality-transferring Ireland–Claisen rearrangement. The method was successfully applied to the synthesis of simple models for the C20 lipid chain/galactosyl glycerol segment of the natural product.

Synthesis Studies on the Lomaiviticin A Aglycone Core: Development of a Divergent, Two-Directional Strategy

The enantiomer of the bicyclic lomaiviticin aglycone A core was prepared via a two-directional, divergent approach featuring (1) a double Ireland Claisen rearrangement to establish key core bonds with correct relative stereochemistry and (2) a double olefin metathesis reaction to deliver both cyclohexene rings of the target.

1,4-Chirality transfer via the ester enolate Claisen rearrangements in the preparation of (25R)- and (25S)-cholestenoic acids

Two variants of the Claisen rearrangement were evaluated for a stereoselective construction of a C-25 stereogenic center in cholestenoic acids based on 1,4-chirality transfer. Johnson orthoester Claisen rearrangement of (22R)- and (22S)-propargyl enol ethers proceeded in a highly stereoselective manner to give (25R)- and (25S)-isomeric allenes. The stereochemical outcome of the Ireland-Claisen rearrangement of 22-allylic alcohols was dependent on the configuration of the C-22 hydroxyl group and the geometry of the enol ether. The latter could be controlled by the solvent (THF or a mixture of THF/HMPA) chosen for the generation of silyl enolate.

Total Synthesis of (−)-α-Kainic acid via Chirality Transfer through Ireland–Claisen Rearrangement

The total synthesis of (-)-α-Kainic acid is accomplished using a linear strategy involving Noyori asymmetric reduction and chirality transfer through Ireland-Claisen rearrangement as key steps.

ChemInform Abstract: Recent Developments in the Reformatsky—Claisen Rearrangement

AbstractReview: 31 refs.

ChemInform Abstract: An Expedient Approach to the Total Synthesis of (+)‐5‐epi‐Eudesm‐4(15)‐ene‐1β,6β‐diol.

AbstractThe title compound (V) is synthesized via an Ireland—Claisen rearrangement of glycolate ester (I) and an intramolecular nitrile oxide cycloaddition [→ (IV)] as key steps.

Novel Concise Synthesis of (−)‐Clausenamide

AbstractA six‐step synthesis of (−)‐clausenamide is described. Optically pure (R,E)‐1,3‐diphenylallylic alcohol was acetylated and then subjected to an Ireland‐Claisen rearrangement, giving the γ,δ‐unsaturated acid, which underwent a substrate‐induced stereoselective bromolactonization to afford the expected all‐equatorial substituted bromo‐δ‐lactone. An unusual chemo‐selective aminolysis of the lactone resulted in the formation of a γ,δ‐epoxy‐amide in stereospecific manner. Base‐promoted cyclization of this intermediate and the subsequent Davis oxidation furnished the synthesis, delivering the final product in >99% ee and up to 34% overall yield.

Asymmetric syntheses of enantiopure C(5)-substituted transpentacins via diastereoselective Ireland–Claisen rearrangements

Asymmetric syntheses of (S,S,S)-2-amino-5-methylcyclopentanecarboxylic acid and (S,S,S)-2-amino-5-phenylcyclopentanecarboxylic acid were achieved in 9 steps from commercially available starting materials via the Ireland-Claisen rearrangement of two enantiopure β-amino allyl esters, followed by ring-closing metathesis, reduction and deprotection.

Towards the enantioselective synthesis of (−)-euonyminol – preparation of a fully functionalised lower-rim model

The development of a stereoselective total synthesis of β-dihydroagarofuran 4 is described. This compound contains the same oxygenation pattern on its 'lower-rim' as found in the natural sesquiterpene (-)-euonyminol (1) and it is expected that the route described should be applicable to the synthesis of that complex natural product. (-)-Euonyminol is found as the core scaffold of a series of complex macrodilactone sesquiterpenoids isolated from the Celastraceae which possess interesting biological activities (e.g. anti-HIV activity). The synthetic route builds upon an epoxidative asymmetric desymmetrisation of meso-diallylic alcohol 10 that we have reported previously. It features a lactate Ireland-Claisen rearrangement to establish the quaternary stereocentre at C11 (27→28a) and an unusual dealkylative intramolecular epoxide-opening by the C11 methyl ether to establish the tetrahydrofuranyl C-ring of the β-dihydroagarofuran skeleton (35→36).

An Ireland–Claisen rearrangement/RCM based approach for the construction of the EF-ring of ciguatoxin 3C

The EF-ring of ciguatoxin 3C, a marine toxin from the dinoflagellate Gambierdiscus toxicus, was stereoselectively synthesized by iterative use of a cyclic ether formation process based on chirality-transferring Ireland-Claisen rearrangement and ring-closing olefin metathesis.

Recent Developments in the Reformatsky-Claisen Rearrangement

The rearrangement of allyl α-bromoacetates with Zn dust is known as the Reformatsky-Claisen rearrangement. Whereas the Ireland-Claisen rearrangement has been widely used in the synthesis of a diverse range of natural products, the Zn-mediated Reformatsky-Claisen rearrangement has not been utilized so often. In this article, we will provide an overview of recent advances in the Reformatsky-Claisen rearrangement field, including the In-mediated Reformatsky-Claisen rearrangement we have recently developed.

Synthesis of a Spirocyclic Seco Structure of the Principal Vetiver Odorant Khusimone

AbstractThe three‐dimensional structure of tricyclic compounds with a zero‐bridge to one bridgehead atom is determined by the underlying spirocyclic framework. (–)‐Khusimone (1), the principal odorant of vetiver oil (content up to 2 %), is such a tricyclic norsesquiterpene, and dissection of the 7,8‐bond between the methylene and the gem‐dimethyl unit of 1 results in a spirocycle extending over an almost identical molecular volume and shape. Given that the “vetiver rule” postulates that one α‐branched carbonyl osmophore in a certain spatial distance to a bulky moiety is responsible for the odor of vetiver, a 7,8‐seco structure of 1 could prove or disprove these structural requirements. Therefore, (4R*,5R*)‐7‐isopropyl‐4‐vinylspiro[4.4]nonan‐1‐one [(4R*,5R*)‐2] was synthesized in a 10‐step synthetic sequence commencing with Steglich esterification of allyl alcohol (15) and isovaleric acid (14). Ireland–Claisen rearrangement of the formed allyl isovalerate (16) with subsequent lithium aluminum hydride reduction of resulting γ,δ‐unsaturated acid 18, Appel bromination of corresponding alcohol 19, and ozonolysis provided 4‐bromo‐3‐isopropylbutanal (23) in 19 % overall yield as a building block for the projected spiroannulation reactions. Although attempts on cyclopentanone (7) failed, cyclopent‐2‐en‐1‐one, via its TMS‐trapped lithium 3‐vinylcyclopent‐1‐enolate 12, turned out to be a successful starting material. Evans' variant of the Mukaiyama aldol reaction with 1‐trimethylsiloxy‐3‐vinylcyclopent‐1‐ene (12) in the presence of BF3·OEt2, followed by palladium‐catalyzed conjugate tin hydride reduction of resulting enone 28 provided 2‐(4′‐bromo‐3′‐isopropylbutyl)‐3‐vinylcyclopentanone (29) in 50 % overall yield as the anlation precursor. LDA‐mediated 5‐exo‐tet cyclization of 29 concluded the synthesis of the racemic 7,8‐seco‐/6‐epi‐7,8‐secokhusimone mixture (4R*,5R*)‐2, which possessed a floral, rosy, green, geranium‐like odor with a threshold of 42.0 ng L–1 air, which is 10 times less intense than that of (–)‐khusimone (1). Most importantly, seco structure (4R*,5R*)‐2 did not display any woody nor any vetiver character, which proves the postulated vetiver rule wrong.

Construction of chiral trifluoromethylated materials by combination of stereochemically predictable SN2′ reaction and Ireland-Claisen rearrangement

We have succeeded in establishment of a novel route for the construction of optically active CF3-containing carboxylic acids in a stereochemically predictable manner starting from easily available mandelic acid by convenient combination of the copper-mediated anti-SN2′ type substitution and Ireland-Claisen rearrangement.

Enantioselective Synthesis of the ent-Lomaiviticin A Bicyclic Core

The bicyclic core of ent-lomaiviticin A was prepared in 11 operations from (S)-1-phenyl-2-propyn-1-ol in a two-directional route that features (1) a double Ireland Claisen rearrangement and (2) a double olefin metathesis reaction to form the key C-C bonds of the target.

Synthesis of Tubuphenylalanines via Ireland–Claisen Rearrangement

The Ireland-Claisen rearrangement is the central step in the synthesis of tubuphenylalanine, a key building block of the highly antitumor-active tubulysins. The rearrangement of substituted β-amino acid allyl esters, in combination with subsequent decarboxylation and oxidative cleavage of the double bond, allows the highly stereoselective introduction of substituents into the α-position of the resulting γ-amino acids.

Practical multigram-scale synthesis of 4,6- and 4,8-sphingadienes, chemopreventive sphingoid bases

Sphingadienes are chemopreventive agents that act by blocking signaling pathways that are activated in cancer. A practical synthesis of 4,6- and 4,8-sphingadienes on a scale of gram quantities is reported here in order to allow evaluation of the biological properties of these sphingolipids. The key steps in the preparation of 4,6-sphingadiene (1a) are an intramolecular cyclization of N-Boc derivative 5a to oxazolidinone derivative 6a, followed by conversion to carbamate intermediate 7a and base-mediated hydrolysis to afford the product without further purification. 4,8-Sphingadiene (1b) was prepared in a similar fashion; the requisite trans-γ,δ-unsaturated aldehyde 15 was prepared by an ester enolate Ireland-Claisen rearrangement.

Total Synthesis of (−)‐Jiadifenin

As easy as ABCD: (-)-Jiadifenin was synthesized in eighteen reaction steps from 1-[(E)-(4'-bromo-2'-butenyl)oxy]-4-methoxybenzene. Key features of this synthesis include: 1) Ireland-Claisen rearrangement to produce the two contiguous quaternary centers at C5 and C6 simultaneously, 2) intramolecular Pauson-Khand reaction (IMPKR) to concurrently construct the A and B rings, and 3) [2+2] photo-cycloaddition to generate the all-carbon quaternary center at C9.

Ireland–Claisen rearrangement of ynamides: stereocontrolled synthesis of 2-amidodienes

The Ireland–Claisen rearrangement of propargyl ynamido ester substrates is reported. The expected allenamide carboxylic acid products from [3,3]-sigmatropic rearrangement are not isolated, with 2-amidodienes alternatively formed in good yield with high levels of stereocontrol after decarboxylation.

ChemInform Abstract: Ireland—Claisen Rearrangement of Secondary Allyl Acetate Revisited: Inevitable C‐Silylation Circumvented by One‐Pot Application of Excessive LDA/TMSCl and TBAF.

AbstractOptimized conditions A) allow the preparation of mixtures which contain the desired unsaturated rearranged acids and silylated analogues of type (III), where the latter are generally formed with higher yields.